Allopregnanolone attenuates inflammation-exacerbated postoperative pain through GABAA receptor–dependent mechanisms in rats

Systemic inflammation can exacerbate postoperative pain. This study investigated whether the neurosteroid allopregnanolone (ALLO), a positive modulator of γ-aminobutyric acid type A (GABA A ) receptors, attenuates inflammation-dependent postoperative pain and whether this effect requires GABA A receptor activity. A rat plantar incision model combined with lipopolysaccharide (LPS)–induced systemic inflammation was used to model sensitized postoperative pain. Pain was assessed using the Rat Grimace Scale (RGS) and von Frey testing. Inflammatory biomarkers in plasma and cerebrospinal fluid (CSF) were analyzed after ALLO and gabazine administration. LPS markedly exacerbated post-incisional spontaneous pain, and ALLO significantly reduced this LPS-induced increase in RGS. This antinociceptive effect was completely abolished by gabazine, supporting a GABA A receptor–dependent mechanism. ALLO did not attenuate LPS-induced elevations of plasma IL-1β or TNF-α. In the CSF, inflammatory cytokines showed no significant group differences; however, CSF S100B, an astrocyte-associated protein, was elevated by LPS and significantly reduced by ALLO. Mechanical withdrawal thresholds were unaffected by LPS or ALLO. Overall, ALLO counteracted inflammation-driven amplification of postoperative pain via a GABA A receptor–dependent mechanism and may represent a neurosteroid-based approach for postoperative pain management in the setting of systemic inflammation.